Mechanisms of Resolution in Acute Vascular Injury

 描述（由申请人提供）：血管内和开放性治疗性血管介入失败是一个非常常见的临床问题，会导致严重的发病率、死亡率和成本。最后一个常见的失败途径是持续性炎症，导致血管壁的增殖和重塑。以前认为炎症的消退是一个被动过程，现在认为是由来自ω-3和ω-6多不饱和脂肪酸（PUFA）的专门促消退脂质介质（PRM）主动控制的。虽然目前的抗再狭窄药物主要通过细胞毒性作用调节增殖，但Conte实验室最近的工作表明，PRM在体外和体内对血管平滑肌细胞（VSMC）产生细胞生长抑制作用。与加州大学旧金山分校的Desai实验室合作，Conte实验室还开发了一种新型的可生物降解的聚合物包裹物，通过这种包裹物，RvD 1可以可靠地输送到局部血管外膜。已经对PRM调节炎症的各种机制进行了大量研究，但是对PRM调节细胞增殖的具体机制知之甚少。我的项目的目标是通过RvD 1（二十二碳六烯酸衍生的，或D系列，resolvin）对血管平滑肌细胞产生细胞抑制作用的机制，特别注意其对血小板衍生生长因子（PDGF）信号通路的影响，在体外和体内。这是一个伟大的临床 由于目前可用的辅助药物疗法受到其细胞毒性作用的限制，因此内源性PRM可能提供一种调节血管愈合的新治疗方法。我的第一个目的是确定RvD 1对兔和人VSMC损伤相关的PDGF扩增途径的影响。将评估VSMC增殖、迁移和白细胞粘附。将通过RNA、蛋白质印迹、免疫染色以及受体表达和磷酸化的测量来评估PDGF表达。我的第二个目的是确定局部外膜递送RVD 1是否改善兔模型血管成形术后重塑，以及该机制是否涉及PDGF扩增途径的衰减。使用新开发的新型可生物降解聚合物包裹物将RvD 1施用于动脉，我将评估早期细胞和分子事件，以及血管成形术后动脉的晚期重塑。通过Conte实验室提供的机会和资源，我个人的目标是为我未来的转化研究和血管生物学职业发展体外和体内技术的基本知识和经验。我希望与博士合作。 Conte将激发和激发我对科学的热情，并帮助我最大限度地发挥我作为未来富有成效和创新的外科医生科学家的潜力。

 DESCRIPTION (provided by applicant): Failure of therapeutic vascular interventions, both endovascular and open, is an exceedingly common clinical problem that incurs significant morbidity, mortality and costs. A final common pathway to failure is persistent inflammation leading to proliferation and remodeling of the vessel wall. The resolution of inflammation, formerly considered a passive process, is now understood to be actively governed by specialized pro-resolving lipid mediators (PRMs) derived from omega-3 and omega-6 polyunsaturated fatty acids (PUFAs). While current anti-restenosis agents modulate proliferation primarily via cytotoxic effects, recent work in the Conte Lab has shown that PRMs exert cytostatic effects on vascular smooth muscle cells (VSMC) both in-vitro and in-vivo. In collaboration with the Desai Lab at UCSF, the Conte Lab has also developed a novel biodegradable polymer wrap through which RvD1 can be reliably delivered to the local vascular adventitia. Much has been studied on the various mechanisms through which PRM's modulate inflammation, however relatively little is known about the specific mechanisms through which PRM's modulate cell proliferation. The goal of my project is to characterize the mechanisms through which RvD1 (a docosahexaenoic acid-derived, or D-series, resolvin) exerts cytostatic effects on vascular smooth muscle cells, with specific attention to its effects on the platelet derived growth factor (PDGF) signaling pathway both in vitro and in vivo. This is of great clinical significance as currently available adjuvant pharmacotherapies are limited by their cytotoxicity effects, and endogenous PRMs may provide a novel therapeutic approach to regulate vascular healing. My first aim is to determine the effects of RvD1 on injury-related PDGF amplification pathways in rabbit and human VSMC. VSMC proliferation, migration, and leukocyte adhesion will be assessed. PDGF expression will be assessed via RNA, western blot, immunostaining as well as measurements of receptor expression and phosphorylation. My second aim is to determine if local adventitial delivery of RVD1 improves post-angioplasty remodeling in a rabbit model, and if the mechanism involves attenuation of PDGF amplification pathways. Using a newly-developed novel biodegradable polymer wrap to administer RvD1 to the artery, I will assess early cellular and molecular events, as well as late remodeling of arteries following angioplasty. Through the opportunities and resources provided by the Conte lab, my personal aim is to develop essential knowledge of and experience with in vitro and in vivo techniques for my future career in translational research and vascular biology. I anticipate that working with Dr. Conte will inspire and invigorate my passion for science and help me maximize my potential as a future productive and innovative surgeon-scientist.